Alzheimer's disease (AD) is the most common cause of dementia and is characterized by accumulation of senile plaques and neurofibrillary tangles in the brain. The primary constituent of senile plaques, amyloid-beta peptide (A), can also be commonly found deposited in brain blood vessels, referred to as cerebral amyloid angiopathy (CAA). CAA can lead to impaired blood vessel integrity and increased risk of brain hemorrhage, and dementia. CAA and AD share common genetic risk factors, including APP mutations and APOE?4. Higher CAA levels are observed in males, while the APOE?4 allele is more significantly associated with CAA in females. These findings suggest that there may be sex- and APOE-dependent pathways that influence the development of AD and/or CAA pathology that are as yet not well understood. Our parent project (RF1 AG051504) aims to close this knowledge gap, where the overarching goal of our work is to address how sex differentially affects cerebrovascular biology, amyloid pathology and CAA formation and how APOE-related and -independent pathways contribute to these sex effects. Under Aim 2 of the parent award, we have collected genome-wide genotypes for 477 individuals, pathologically diagnosed with AD, and scored for CAA pathology. We obtained RNAseq expression measures in temporal cortex of all and in cerebellum of a subset (N=200) of these same individuals. Further, we are in the process of also collecting DNA methylation (RRBS), and histone acetylation (H3K27ac) measures from many of these same tissue samples. Biochemical measures, including brain apoE and A levels are likewise being collected. Thus, we are well positioned to perform integrative molecular profiling analysis on this autopsy cohort, and have already made significant progress. We completed GWAS of CAA and confirmed APOE?4 dose as a significant risk factor in our cohort (p=4.85E-14). Sex stratified analysis confirmed more significant association for APOE?4 dose in females than males. Importantly, we identified 184 independent loci with a smaller p-value than those at the APOE locus (p<1.16E-06) in males. Upon further stratification, it is clear that the largest difference between CAA in males and females is observed for APOE?33 homozygotes. These findings suggest presence of sex- and APOE- specific genetic factors that influence CAA and if replicated can identify novel pathways that contribute to both CAA and AD. In this administrative proposal, our overarching goal is to increase our power to identify such genetic variants and pathways. We plan to achieve this by performing GWAS in an additional 350 AD samples with CAA scores and readily available brain samples. We have all the technical and analytic tools to accomplish this aim which is entirely aligned with our parent proposal. We expect the outcomes of this administrative supplement to enhance our power to detect genetic variants and novel pathways contributing to CAA and AD. Further, any existing or future biochemical, neuropathology, proteomic or other measures on this additional cohort, can be analyzed for genetic associations, thereby leading to far-reaching additional benefits.